21-bromo steroids



Patented Dec. 23, 1952 21-BROMO STEROIDS Edward C. Kendall, Rochester, Minn., assignor to Research Corporation, New York, N. Y., a corporation of New York No Drawing. Application January 3, 1950, Serial No. 136,659

4 Claims.

, ed to the bile acids, that is, having a steroid structure, and having at the 17-position a five carbon chain with a double bond at position 20, 22 and a methyl group at position 20, e. g., bile acids, cholic acid, desoxycholic acid, lithocholic acid and the 3,9-epoxy derivatives as disclosed in my application Serial No. 653,176, filed March 8, 1946, now Patent No. 2,541,074.

The essentialconditions of the process for the introduction'of bromine at the 2l-position are the use of an anhydrous organic solvent such as carbon'tetrachloride, the presence of bromosuc- 'cin'imide in the reaction mixture and boiling the "mixture while it is subjected to illumination.

As is disclosed in said application the 3(a)- 3(a) acetoxy-ll-keto-12-bromo-24,24-diphenyl- A?= cho1adiene 3(a) -acetoXy-11-l eto-12-bromo-24,24 diphenyl- (31) is prepared from A -cholene (29) by treatment with one molar equivalent of bromosuccinimide in the presence of light, This treatment results in the introduction of bromine in position 22 giving a compound represented by Formula 30 in said application, iIfeI, 3(a) -acetoxy-'11-keto 12,22-dibromo-24,24- "diphenyl-A -cholene and when this bromo derivativ is heated in carbon tetrachloride,fhydroof the compound to be treated.

2 gen bromide is eliminated with formation of a double bond 20:22 (Compound 31).

It has now been found that the resulting diene (31) will react with a second mole of bromosuccinimide in the presence of light with the formation of the 21-bromo derivative thereof (Compound I) which can be separated in pure form by crystallization from ligroin.

The bromo group at C21 in the diene I'is readily replaced by the acetoxyl group by treatment with sodium acetate in acetic acid to give 3 (a) ,2l-diacetoXy-11-keto- 12 -brom0 24,24 diphenyl-A -choladiene (Compound II). In methanol, Compound I is converted into the .cor-

responding 2l-methoxy compound and the acetyl method the S-acetoXy group is changed t va ketone to give 3,11-diketo-12-bromo-21-methoXy- 24,24- diphenyl-A P=?? -choladiene, Compound While it is desirable that the 3-OH group be I protected by acylation during the treatment with bromosuccinimide, the nature of the acyl radical is not important and other acids than acetic acid may be utilized to acylate the 3-OH, for example, propionic, benzoic or p-nitrobenzoio acids, the corresponding 3-acyl-21-bromo compound (I) being formed.

The 3-OI-I group may also be protected during the reaction by forming the 3,9-epoxy derivative 3 Compounds I to V are illustrated in the following flow sheet:

The following is a typical example of the process:

Preparation of 3(a) acetoacy-lI-lceto-IZJJ-dibromo-24,24-diphenyZ-A -choladiene (I) following maximum: in CCl4 at 310 mu, e=20,800 H (E=330); in MeOH (+1% C014) at 304 mu,

e=20,600 (E:328). Since for 3,9-ep0xy-11-keto- 24,24-diphenyl-A -choladiene e is 28,800 (E=518) at 304 mu in MeOH and since for the 21-acetoxy and 21-methoxy derivatives of 3(a)- acetoxy l1 keto 12 bromo 24,24 diphenyl- A -choladiene e is 27,000 at 305 mu, it must be assumed that the above material contains only approximately '75 per cent diene (31).

The crude diene (31) obtained from 80 g. of the ethylene (29) was dissolved in 960 m1. carbon tetrachloride, mixed with 23.52 g. of 96 per cent bromosuccinimide and boiled for 20 minutes over a light bulb, cooled and filtered. The filtrate was brought to almost complete dryness and petroleum ether added. 63.0 g. (70.2 per cent) of crystalline material separated. Recrystallization from about 200 m1. hot benzene and 200 ml. hot petroleum ether yielded a first crop of 49.0 g. (54.7 per cent) with E==377 at 325 mu in chloroform and a second crop of 6.6 g. (6.9 per cent) with E=364.

Preparation of 3(a),21-dilZC6t01311-11-7C6t0 12 bromo 24,24 diphenyl A cholaaiene (II) from the corresponding 21 -br0rno compound (I) 1.42 g. of the bromo compound and 12 ml. of N/3 sodium acetate in glacial acetic acid was kept on the steam bath with intermittent shaking for 1 hours. After cooling the reaction product was taken up in chloroform, washed with water, then sodium bicarbonate and again water, dried and evaporated. When methanol was added to the residue it crystallized immediately. Yield 1.01 g. (74 per cent); the unfractionated reaction product had E=410 at 310 mu in chloroform. For the pure compound, M. P. 180-181; (a) (1 per cent in acetone); +79 (1 per cent in chloroform).

Preparation of 3(a)-0LC6tO$ZJ-21-17Z6ULO.LZ/-11lto 12- Memo-24,24-diphenyZ-A -choladiene (IV) from the corresponding 21-bromo compound (I) When the bromo compound, dissolved in a little chloroform is mixed with methanol, the extinction maximum of the former changes immediately from about 323 mu to 305 mu and the extinction coefficient from e=27,000 (E=382) to e=11,000. If, however, some HBr is present, the extinction coefiicient will remain about 27,000 (at 305 mu). In either case, all the bromine from position 21 is now present as bromide ion. In the former case a partial allylic shift is assumed to take place. The mixture of the isomeric methoxy compounds has not been separated.

7.08 g. of bromo compound dissolved in 150 ml. chloroform was mixed with 300 m1. N/3 HBr in MeOI-I and allowed to stand at room temperature overnight. Chloroform was added and the organic phase was washed thoroughly with water. The reaction product separated as a solid from dilute methanol, M. P. 101105, but was present as an oil with non-polar solvents. It was reacetylated in position 3 with acetic anhydride and pyridine which yielded the crystalline 3-acetoxy-21-methoxy derivative in 85 per cent yield, M. P. 179-180 (depression with the diacetate); (a) =+1O3 (1 per cent in acetone), +92 (1 per cent in chloroform).

Preparation of 21 -methoxy-3,1 1 -diketo-1 2-122-0- mo-24,24-diphenyl-A fl -choladi'ene (V) 1.86 g. 3(a) -hydroxy-21-methoxy-11-keto-12- bromo-24,24-dipheny1-A -cho1adiene (III), 5.6 g. t. aluminum butoxide, 68 ml. acetone and 225 ml. dry benzene were refluxed for hours. The benzene solution was washed with a solution of Rochelle salt, sodium carbonate and water. The benzene was removed.

The reaction product crystallized after the addition of methanol. Yield 1.28 g. of short needles, M. P. 167-169. After six recrystallizations from acetone-methanol M. P. 1'78180, (u) +78 (1 per cent in acetone) +70 (1 per cent in chloroform). e=27,000 (E=439) at 305 mu. The mother liquor crystallized after steam distillation and had the same extinction coefficient, but the melting point suggested a mixture of 3-keto and 3-hydroxy compound.

Preparation of the 21-bromo derivative of 3,9-

epowy 11 keto 24,24 diphenylcholadiene- A20.'ZZ,23:24

17.8 gm. of 3,9-epoxy-11-keto-24,24-diphenylcholene-A were dissolved in 260 m1. of pure carbon tetrachloride to which were added 6.486 gm. of bromosuccinimide (96 per cent). The carbon tetrachloride was refluxed over a 200-watt light bulb for twenty minutes and was heated on a steam bath for six hours to eliminate hydrogen bromide. Another portion of bromosuccinimide, 6.486 gm., was added and the solution was again refluxed for fifteen minutes under the same conditions. The solution was filtered. The filtrate was concentrated practically to dryness and petroleum ether was added. After several hours in the cold room crystals separated and were filtered. Further crops were obtained by concentration to dryness, dissolving the residue in a small amount of chloroform and adding ligroin. 8.76 gm. of crystals were secured. The melting point depended upon the rate of heating. When placed on the melting point apparatus at 234 the melting point was 236-240". When the stage was heated to 240 the melting point after one minute was 241-243. When added at 245 the melting point was 246. =28,500 at mu 324.

This application is a continuation-in-part of my application Serial No. 734,867, filed March 14, 1947, now abandoned.

I claim:

1. A 3(a) acyloxy-ll-keto 12,21 dibromo- 24,24-diphenyl-A -choladiene wherein the acyl group is selected from lower fatty acids and monocyclic aryl monocarboxylic acids.

2. 3(a) acetoxy 11 keto 12,21 dibromo 24,24-diphenyl-A -choladiene.

3. Process which comprises mixing a 3(a) acyloxy 11 keto 12 bromo 24,24-dipheny1 A -choladiene with bromosuccinimide in an inert anhydrous organic solvent for the reactants and heating the mixture while subjecting it to illumination to produce the corresponding 21-bromo compound.

4. Process which comprises mixing a 3(a) acetoxy 11 keto 12 bromo 24,24-diphenyl- A -choladiene with bromosuccinimide in an inert anhydrous organic solvent for the reactants and heating the mixture while subjecting it to illumination to produce the corresponding 21-bromo compound.

EDWARD C. KENDALL.

REFERENCES CITED The following references are of record in the file of this patent:

Wettstein, Helv. Chim. Acta 30, 1262-1269 (1947). 

1. A 3(A) - ACYLOXY-11-KETO - 12,21 - DIBROMOACYL GROUP IS SELECTED FROM LOWER FATTY ACIDS AND MONOCYCLIC ARYL MONOCARBOXYLIC ACIDS. 